title: [Comprehensive synthetic study of muraymycins toward the development of novel antibacterial agents].
abstract: This review describes the synthesis and structure-activity relationship (SAR) study of muraymycins (MRYs), which are potent antibacterial nucleoside antibiotics. The key elements of our synthetic approach include the preparation of L-epi-capreomycidine via a C-H amination reaction and a convergent assemblage to construct of the framework of MRYs using Ugi four component reaction. With this approach the first total synthesis of MRY D2 and its epimer, epi-MRY D2, which does not have lipophilic substituents, has been accomplished. The fact that MRY D2 and it's epimer did not show any antibacterial activity indicated the lipophilic substituents of MRYs plays an important role in membrane-permeability. Hence, MRY analogues with lipophilic substituents were designed and synthesized simply by altering the aldehyde component in Ugi four-component assemblage. The MRY analogues with lipophilic substituents exhibited improved antibacterial activity against anti drug-resistant bacteria. It was also suggested that the accessory urea-dipeptide motif might contribute to MraY inhibitory and antibacterial activity. Our synthetic approach would effectively provide a variety of MRY analogues and resultant SAR information brings us directions to create further MRY analogues.
authors.affiliation: Graduate School of Life Science, Hokkaido University. tetuya@mail.sci.hokudai.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tanino
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Uotani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Oyama
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D009705:Nucleosides; D010455:Peptides; C549119:muraymycin D2